Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers

On the behalf of the Radiogenomics Consortium; Elnaz Naderi; Miguel E Aguado-Barrera; Line M H Schack; Leila Dorling; Tim Rattay; Laura Fachal; Holly Summersgill; Laura Martínez-Calvo; Ceilidh Welsh; Tom Dudding; Yasmin Odding; Ana Varela-Pazos; Rajesh Jena; David J Thomson; Roel J H M Steenbakkers; Joe Dennis; Ramón Lobato-Busto; Jan Alsner; Andy Ness; Chris Nutting; Antonio Gómez-Caamaño; Jesper G Eriksen; Steve J Thomas; Amy M Bates; Adam J Webb; Ananya Choudhury; Barry S Rosenstein; Begona Taboada-Valladares; Carsten Herskind; David Azria; David P Dearnaley; Dirk de Ruysscher; Elena Sperk; Emma Hall; Hilary Stobart; Jenny Chang-Claude; Kim De Ruyck; Liv Veldeman; Manuel Altabas; Maria Carmen De Santis; Marie-Pierre Farcy-Jacquet; Marlon R Veldwijk; Matthew R Sydes; Matthew Parliament; Nawaid Usmani; Neil G Burnet; Petra Seibold; R Paul Symonds; Johannes A Langendijk; Behrooz Z Alizadeh

doi:10.1093/jncics/pkad088

Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers

On the behalf of the Radiogenomics Consortium, Elnaz Naderi, Miguel E Aguado-Barrera, Line M H Schack, Leila Dorling, Tim Rattay, Laura Fachal, Holly Summersgill, Laura Martínez-Calvo, Ceilidh Welsh, Tom Dudding, Yasmin Odding, Ana Varela-Pazos, Rajesh Jena, David J Thomson, Roel J H M Steenbakkers, Joe Dennis, Ramón Lobato-Busto, Jan Alsner, Andy NessChris Nutting, Antonio Gómez-Caamaño, Jesper G Eriksen, Steve J Thomas, Amy M Bates, Adam J Webb, Ananya Choudhury, Barry S Rosenstein, Begona Taboada-Valladares, Carsten Herskind, David Azria, David P Dearnaley, Dirk de Ruysscher, Elena Sperk, Emma Hall, Hilary Stobart, Jenny Chang-Claude, Kim De Ruyck, Liv Veldeman, Manuel Altabas, Maria Carmen De Santis, Marie-Pierre Farcy-Jacquet, Marlon R Veldwijk, Matthew R Sydes, Matthew Parliament, Nawaid Usmani, Neil G Burnet, Petra Seibold, R Paul Symonds, Johannes A Langendijk, Behrooz Z Alizadeh

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Abstract

BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity (RIT) across four cancer types (prostate, head and neck, breast, and lung).

METHODS: A GWAS meta-analysis was performed using 19 cohorts including 12,042 patients. Acute standardized total average toxicity (rSTATacute) was modelled using a generalized linear regression model for additive effect of genetic variants adjusted for demographic and clinical covariates. LD score regression estimated shared SNP-based heritability of rSTATacute in all patients and for each cancer type.

RESULTS: Shared SNP-based heritability of STATacute among all cancer types was estimated at 10% (se = 0.02), and was higher for prostate (17%, se = 0.07), head and neck (27%, se = 0.09), and breast (16%, se = 0.09) cancers. We identified 130 suggestive associated SNPs with rSTATacute (5.0x10-8<P-value<1.0x10-5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size -0.17; P-value=1.7x10-7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 x10-6, Pcorrected =0.079) as the top gene set associated with rSTATacute among all patients. In-silico gene expression analysis showed the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed Pcorrected=0.004; sun exposed Pcorrected=0.026).

CONCLUSIONS: There is shared SNP-based heritability for acute RIT across and within individual cancer sites. Future meta-GWAS among large radiotherapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

Original language	English
Article number	pkad088
Number of pages	11
Journal	JNCI cancer spectrum
Volume	7
Issue number	6
Early online date	20-Oct-2023
DOIs	https://doi.org/10.1093/jncics/pkad088
Publication status	Published - Dec-2023

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Large-scale meta–genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types Final publisher's version, 1.19 MBLicence: CC BY-NC

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On the behalf of the Radiogenomics Consortium, Naderi, E., Aguado-Barrera, M. E., Schack, L. M. H., Dorling, L., Rattay, T., Fachal, L., Summersgill, H., Martínez-Calvo, L., Welsh, C., Dudding, T., Odding, Y., Varela-Pazos, A., Jena, R., Thomson, D. J., Steenbakkers, R. J. H. M., Dennis, J., Lobato-Busto, R., Alsner, J., ... Alizadeh, B. Z. (2023). Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers. JNCI cancer spectrum, 7(6), Article pkad088. https://doi.org/10.1093/jncics/pkad088

@article{17d65d70ac9b4bf9bccad6c1e48b74ad,

title = "Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers",

abstract = "BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity (RIT) across four cancer types (prostate, head and neck, breast, and lung).METHODS: A GWAS meta-analysis was performed using 19 cohorts including 12,042 patients. Acute standardized total average toxicity (rSTATacute) was modelled using a generalized linear regression model for additive effect of genetic variants adjusted for demographic and clinical covariates. LD score regression estimated shared SNP-based heritability of rSTATacute in all patients and for each cancer type.RESULTS: Shared SNP-based heritability of STATacute among all cancer types was estimated at 10% (se = 0.02), and was higher for prostate (17%, se = 0.07), head and neck (27%, se = 0.09), and breast (16%, se = 0.09) cancers. We identified 130 suggestive associated SNPs with rSTATacute (5.0x10-8CONCLUSIONS: There is shared SNP-based heritability for acute RIT across and within individual cancer sites. Future meta-GWAS among large radiotherapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.",

author = "{On the behalf of the Radiogenomics Consortium} and Elnaz Naderi and Aguado-Barrera, {Miguel E} and Schack, {Line M H} and Leila Dorling and Tim Rattay and Laura Fachal and Holly Summersgill and Laura Mart{\'i}nez-Calvo and Ceilidh Welsh and Tom Dudding and Yasmin Odding and Ana Varela-Pazos and Rajesh Jena and Thomson, {David J} and Steenbakkers, {Roel J H M} and Joe Dennis and Ram{\'o}n Lobato-Busto and Jan Alsner and Andy Ness and Chris Nutting and Antonio G{\'o}mez-Caama{\~n}o and Eriksen, {Jesper G} and Thomas, {Steve J} and Bates, {Amy M} and Webb, {Adam J} and Ananya Choudhury and Rosenstein, {Barry S} and Begona Taboada-Valladares and Carsten Herskind and David Azria and Dearnaley, {David P} and {de Ruysscher}, Dirk and Elena Sperk and Emma Hall and Hilary Stobart and Jenny Chang-Claude and {De Ruyck}, Kim and Liv Veldeman and Manuel Altabas and {De Santis}, {Maria Carmen} and Marie-Pierre Farcy-Jacquet and Veldwijk, {Marlon R} and Sydes, {Matthew R} and Matthew Parliament and Nawaid Usmani and Burnet, {Neil G} and Petra Seibold and Symonds, {R Paul} and Langendijk, {Johannes A} and Alizadeh, {Behrooz Z}",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press.",

year = "2023",

month = dec,

doi = "10.1093/jncics/pkad088",

language = "English",

volume = "7",

journal = "JNCI cancer spectrum",

issn = "2515-5091",

publisher = "Oxford University Press",

number = "6",

}

On the behalf of the Radiogenomics Consortium, Naderi, E, Aguado-Barrera, ME, Schack, LMH, Dorling, L, Rattay, T, Fachal, L, Summersgill, H, Martínez-Calvo, L, Welsh, C, Dudding, T, Odding, Y, Varela-Pazos, A, Jena, R, Thomson, DJ, Steenbakkers, RJHM, Dennis, J, Lobato-Busto, R, Alsner, J, Ness, A, Nutting, C, Gómez-Caamaño, A, Eriksen, JG, Thomas, SJ, Bates, AM, Webb, AJ, Choudhury, A, Rosenstein, BS, Taboada-Valladares, B, Herskind, C, Azria, D, Dearnaley, DP, de Ruysscher, D, Sperk, E, Hall, E, Stobart, H, Chang-Claude, J, De Ruyck, K, Veldeman, L, Altabas, M, De Santis, MC, Farcy-Jacquet, M-P, Veldwijk, MR, Sydes, MR, Parliament, M, Usmani, N, Burnet, NG, Seibold, P, Symonds, RP, Langendijk, JA & Alizadeh, BZ 2023, 'Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers', JNCI cancer spectrum, vol. 7, no. 6, pkad088. https://doi.org/10.1093/jncics/pkad088

TY - JOUR

T1 - Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers

AU - On the behalf of the Radiogenomics Consortium

AU - Naderi, Elnaz

AU - Aguado-Barrera, Miguel E

AU - Schack, Line M H

AU - Dorling, Leila

AU - Rattay, Tim

AU - Fachal, Laura

AU - Summersgill, Holly

AU - Martínez-Calvo, Laura

AU - Welsh, Ceilidh

AU - Dudding, Tom

AU - Odding, Yasmin

AU - Varela-Pazos, Ana

AU - Jena, Rajesh

AU - Thomson, David J

AU - Steenbakkers, Roel J H M

AU - Dennis, Joe

AU - Lobato-Busto, Ramón

AU - Alsner, Jan

AU - Ness, Andy

AU - Nutting, Chris

AU - Gómez-Caamaño, Antonio

AU - Eriksen, Jesper G

AU - Thomas, Steve J

AU - Bates, Amy M

AU - Webb, Adam J

AU - Choudhury, Ananya

AU - Rosenstein, Barry S

AU - Taboada-Valladares, Begona

AU - Herskind, Carsten

AU - Azria, David

AU - Dearnaley, David P

AU - de Ruysscher, Dirk

AU - Sperk, Elena

AU - Hall, Emma

AU - Stobart, Hilary

AU - Chang-Claude, Jenny

AU - De Ruyck, Kim

AU - Veldeman, Liv

AU - Altabas, Manuel

AU - De Santis, Maria Carmen

AU - Farcy-Jacquet, Marie-Pierre

AU - Veldwijk, Marlon R

AU - Sydes, Matthew R

AU - Parliament, Matthew

AU - Usmani, Nawaid

AU - Burnet, Neil G

AU - Seibold, Petra

AU - Symonds, R Paul

AU - Langendijk, Johannes A

AU - Alizadeh, Behrooz Z

PY - 2023/12

Y1 - 2023/12

N2 - BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity (RIT) across four cancer types (prostate, head and neck, breast, and lung).METHODS: A GWAS meta-analysis was performed using 19 cohorts including 12,042 patients. Acute standardized total average toxicity (rSTATacute) was modelled using a generalized linear regression model for additive effect of genetic variants adjusted for demographic and clinical covariates. LD score regression estimated shared SNP-based heritability of rSTATacute in all patients and for each cancer type.RESULTS: Shared SNP-based heritability of STATacute among all cancer types was estimated at 10% (se = 0.02), and was higher for prostate (17%, se = 0.07), head and neck (27%, se = 0.09), and breast (16%, se = 0.09) cancers. We identified 130 suggestive associated SNPs with rSTATacute (5.0x10-8CONCLUSIONS: There is shared SNP-based heritability for acute RIT across and within individual cancer sites. Future meta-GWAS among large radiotherapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

AB - BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity (RIT) across four cancer types (prostate, head and neck, breast, and lung).METHODS: A GWAS meta-analysis was performed using 19 cohorts including 12,042 patients. Acute standardized total average toxicity (rSTATacute) was modelled using a generalized linear regression model for additive effect of genetic variants adjusted for demographic and clinical covariates. LD score regression estimated shared SNP-based heritability of rSTATacute in all patients and for each cancer type.RESULTS: Shared SNP-based heritability of STATacute among all cancer types was estimated at 10% (se = 0.02), and was higher for prostate (17%, se = 0.07), head and neck (27%, se = 0.09), and breast (16%, se = 0.09) cancers. We identified 130 suggestive associated SNPs with rSTATacute (5.0x10-8CONCLUSIONS: There is shared SNP-based heritability for acute RIT across and within individual cancer sites. Future meta-GWAS among large radiotherapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

U2 - 10.1093/jncics/pkad088

DO - 10.1093/jncics/pkad088

M3 - Article

C2 - 37862240

SN - 2515-5091

VL - 7

JO - JNCI cancer spectrum

JF - JNCI cancer spectrum

IS - 6

M1 - pkad088

ER -

Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers

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